IL-6 transsignalling modulates the early effector phase of EAE and targets the blood-brain barrier.
Interleukin-6 (IL-6) plays a crucial role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). It exerts its cellular effects by a membrane-bound IL-6 receptor (IL-6R), or, alternatively, by forming a complex with the soluble IL-6R (sIL-6R), a process named IL-6 transsignalling. Here we investigate the role of IL-6 transsignalling in myelin basic protein (MBP)-induced EAE in the Lewis rat. In vivo blockade of IL-6 transsignalling by the injection of a specifically designed gp130-Fc fusion protein significantly delayed the onset of adoptively transferred EAE in comparison to control rats injected with PBS or isotype IgG. Histological evaluation on day 3 after immunization revealed reduced numbers of T cells and macrophages in the lumbar spinal cord of gp130-Fc treated rats. At the same time, blockade of IL-6 transsignalling resulted in a reduced expression of vascular cell adhesion molecule-1 on spinal cord microvessels while experiments in cell culture failed to show a direct effect on the regulation of endothelial adhesion molecules. In experiments including active EAE and T cell culture, inhibition of IL-6 transsignalling mildly increased T cell proliferation, but did not change severity of active MBP-EAE or regulate Th1/Th17 responses. We conclude that IL-6 transsignalling may play a role in autoimmune inflammation of the CNS mainly by regulating early expression of adhesion molecules, possibly via cellular networks at the blood-brain barrier.
Linker
Ralf A
RA
Department of Neurology, St. Josef Hospital Bochum, Ruhr-University Bochum, Bochum, Germany. ralf.linker@rub.de
Lühder
Fred
F
Kallen
Karl-Josef
KJ
Lee
De-Hyung
DH
Engelhardt
Britta
B
Rose-John
Stefan
S
Gold
Ralf
R
D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D016466:CHO Cells; D049109:Cell Proliferation; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D050822:Cytokine Receptor gp130 / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006168:Guinea Pigs; D015850:Interleukin-6 / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D016207:Cytokines; D015850:Interleukin-6; D004676:Myelin Basic Protein; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130